The intervertebral disc (IVD) is the largest avascular structure in the body, and IVD cells reside in vivo in an environment that is considered to be hypoxic. However, the role of oxygen in IVD cell biology remains an issue of debate. By reviewing the available literature about the effect of oxygen tension on regulating the phenotype, energy metabolism, matrix production, and survival of IVD cells, as well as on the expression and function of hypoxia-inducible factor in IVD cells, we conclude that hypoxia is essential in maintaining the physiological function of IVD cells. Modulating the oxygen tension of the IVD or the activity of hypoxia-inducible factor in IVD cells may be a promising strategy for the prevention and treatment of IVD degeneration.